Disorders of skeletal muscle characterized by degeneration of muscle make up the family of muscular dystrophies, aging associated sarcopenia and cancer cachexia. Development of stem cell based therapies for the muscular dystrophies aim to replace the pool of skeletal muscle stem cells required for muscle regeneration. For long-term stem cell based therapy to be effective, transplanted stem cells must not only contribute to the regeneration of healthy muscle, but must also ‘self-renew’ and be present throughout the lifetime of the individual. The importance of self-renewal is illustrated by the total failure of engrafted myoblasts, which lost the stem-cell capacity to self-renew, to provide any benefit to the muscle of patients with Duchenne muscular dystrophy in early clinical trials performed in the 1990s. These failures indicate that strategies are necessary to optimize the self-renewal capacity of skeletal muscle stem cells both during ex vivo expansion and after their engraftment. We aim to identify small molecule compounds that enhance the self-renewal capacity of skeletal muscle stem cells, which would permit their expansion ex vivo and also improve their ability to restore the satellite cell compartment after their engraftment in vivo. We have identified phosphorylated eIF2α to be present in skeletal muscle stem cells. Upon activation of skeletal muscle stem cells, eIF2α is rapidly dephosphorylated. We show that pharmacological inhibition of eIF2α dephosphorylation promotes skeletal muscle stem cell self-renewal and expansion.